As disclosed in Japanese Patent Publication 45-29369 and in U.S. Pat. Nos. 3,755,427, 3,901,906, 3,959,364, 4,266,069, 4,278,516 and 4,324,904, there is a variety of known techniques for the preparation of flurbiprofen, i.e., 2-(2-fluoro-4-biphenylyl)propionic acid, and similar compounds having desirable anti-inflammatory, analgesic, and anti-pyretic properties. Some particularly interesting techniques are taught in U.S. Pat. No. 3,901,906 (Kozlik), which discloses that flurbiprofen and similar materials can be prepared from fluoroaralkyloxazolines, such as 2-[1-(2-fluoro-4-biphenylyl)ethyl]-4,4-dimethyloxazoline, which in turn may be prepared, e.g., by (1) reacting an appropriate arylmagnesium halide or aryllithium with a 2-haloalkyl-4,4-disubstituted oxazoline, (2) reacting an aryl halide with a 4,4-disubstituted oxazolinylalkyllithium or a 4,4-disubstituted oxazolinylalkylmagnesium halide, or (3) reacting an appropriate aralkanoic acid with a suitable aminoalkanol.
Unfortunately, the conventional techniques of preparing these flurbiprofen-type compounds have the disadvantage of being tedious and time-consuming. It would obviously be a welcome contribution to the art to provide a method of synthesizing the compounds, as well as intermediates therefor, in a simple, straightforward manner.
U.S. Pat. No. 4,370,278 (Stahly et al.) and copending applications Ser. No. 452,518 (Barbara Clark Stahly et al.) and Ser. No. 452,617 (G. Patrick Stahly et al.), filed Dec. 23, 1982, disclose such improved syntheses wherein the intermediates are prepared by nucleophilic substitution processes utilizing nitrile and ester nucleophiles. These processes have decided advantages over the prior art but have the disadvantage of utilizing nucleophiles which tend to lead to excessive by-product formation.